Prodrugs of peptides. 11. Chemical and enzymatic hydrolysis kinetics of N-acyloxymethyl derivatives of a peptide-like bond

Various carboxylic acid esters of the N-hydroxymethyl derivative of N-benzyloxycarbonylglycine benzylamide, used as a peptide-like model, were prepared and their decomposition kinetics studied in aqueous solution and in human plasma solutions. These N-acyloxymethylamide derivatives were found to undergo a facile decomposition by a pH-independent process in the pH range 4-8.5, the half-lives being 1-11hr at 37 degrees C. The cause of this limited stability was suggested to be due to the occurrence of an elimination-addition mechanism involving a reactive N-acylminium ion intermediate. In alkaline solutions (pH greater than 10) the derivatives showed a normal ester stability. The ester group in the N-acyloxymethyl derivatives was readily hydrolyzed by plasma enzymes to yield the N-hydroxymethyl amide, which subsequently decomposed to the parent amide. The results obtained suggest that N-acyloxymethylation of a peptide bond may be a useful prodrug approach to obtain derivatives with varying lipophilicities and a ready ability to undergo conversion to the parent peptide in vivo. However, the stability of the derivatives in aqueous solutions is limited.